The recent dramatic rise in methamphetamine (METH)-related trafficking, emergency room visits, and deaths has been declared a severe national crisis by the U.S. Department of justice. Because of these disturbing trends in heavy METH abuse, it is important to elucidate the causes of METH-induced long-term deficits to striatal monoaminergic systems. It has been demonstrated that METH dramatically increases extracellular dopamine (DA) and the large quantities of the released DA in the presence of O2 and reactive iron, may oxidize to form cytotoxic free radicals. Because of the reactive nature of DA, and the finding of this and other laboratories that the formation of reactive oxygen species (ROS) correlates with METH- induced monoaminergic changes, we hypothesize that: Generation of DA- related ROS is a major contributor to the neurochemical deficits occurring in striatal monoaminergic systems after high doses of METH. This hypothesis will be tested by monitoring drug-induced changes in monoamine neurochemical parameters and oxidation products of salicylate in order to achieve the following Specific Aims: Specific Aim A. Establish the optimal conditions to assess ROS generation after METH administration to (a) confirm that high doses of METH increase ROS formation, (b) correlate ROS formation with METH-induced monoamine deficits and (c) identify experimental conditions for the remainder of the studies. Specific Aims B and C. Determine if factors that alter METH-induced monoamine deficits influence its ability to produce ROS (Specific Aim B) and determine if factors that are associated with ROS production from DA influence METH-induced monoamine deficits (Specific Aim C). These studies will help link METH-induced ROS formation and monoamine deficits as well as elucidate related mechanisms. Specific Aim D. Demonstrate that besides the well-established long-term monoamine deficits, increased ROS caused by high doses of METH also effect dramatic, rapid, but reversible, reductions in DA transporter activity. This exciting new finding will be characterized and the role of ROS in this effect examined. These studies will elucidate the role of DA-related ROS in monoamine responses to the abuse of high doses of METH and provide insight into the mechanisms associated with DA-linked neurological diseases, such as Parkinson's disease.